Anthelmintic (isothiocyanophenyl) oxadiazoles

ABSTRACT

(Isothiocyanophenyl) oxadiazoles and related compounds and their methods of preparation are disclosed. In addition, useful compositions and methods for employing said compositions as anthelmintics are taught.

United States Patent Narayanan et al. Oct. 7, 1975 ANTHELMINTIC [51]Int. Cl. C07D 271/06 (ISOTHIOCYANOPHENYL) OXADIAZOLES [58] Field ofSearch 260/307 G [75] Inventors: Venkatachala L. Narayanan,

Hightstown; Anthony Joseph [56] References C'ted Martinez, Princeton;Rudiger D. UNITED STATES PATENTS Haugwitz, Titusville, all of 3,853,89312/1974 Narayanan et al 260/294.8 E [73] Assignee: E. R. Squibb & Sons,Inc., I

Princeton, NJ Primary ExammerRaymond V. Rush Attorney, Agent, orFirmLawrence S. Levinson; [22] Flled: July 1974 Merle J. Smith; StephenB. Davis [21] Appl. No.2 487,497

57 ABSTRACT Related U.S. Application Data E 1 h l d l t d so locyanopeny oxa iazo es an re a e com- [63] (llggmuation-m-part of Ser. No.347,313, Apnl 2, pounds and their methods of preparation are abandoned.

closed. In addition, useful compositions and methods [52] Clum 260/307G; 260,544 L; 260/544 M; for employing said compositions asanthelmintics are 260/544 Y, 260/546; 260/562 R; 260/564 G; 424/272taught.

13 Claims, No Drawings SCN wherein R is hydrogen, lower alkyl, aryl,halogen, trifluoromethyl, lower alkoxy, aryloxy, di(lower alkyl)- aminoand lower alkyl 0 H l l R is hydrogen, lower alkyl, cycloalkyl, aryl,halolower alkyl. and adamantyl.

In addition, this invention encompasses the methods for preparing said(isothiocyanophenyl)oxadiazoles, compositions containing said(isothlocyanophenyl)oxadiazoles and methods for using said compositionsanthelmintic agents.

Lastly, this invention is intended to also include the intermediatesutilized in preparing said anthelmintic (isothiocyanophenyl)oxadiazoles.

The term aryl is intended to include phenyl, naphthyl, substitutedphenyl wherein said substituent may be one or more of fluoro, chloro,bromo, iodo, nitro, trifluoromethyl, lower alkyl and lower alkoxy.

The term lower alkyl is intended to mean a straight or branchedhydrocarbon fragment of from one to ten carbon atoms, preferably 1 to 4,such as methyl, propyl, t-butyl, etc.

Cycloalkyl includes ring systems of 3 to 6 carbon atoms such ascyclopropyl, cyclopentyl, cyclohexyl,

etc.

The term lower alkoxy" is intended to mean a lower alkyl group linkedthrough a single bond to oxygen.

The term halo or halogen" is intended to mean chloro or bromo."

The compounds of this invention are prepared in the following manner.

II III The nitrobenzonitriles of formula II are converted to amidoximesof the formula III by treatment with an acid salt of hydroxylamine, suchas the hydrochloride, sulfate or phosphate in the presence of an acidacceptor, such as sodium or potassium carbonate. The reaction isgenerally conducted in an aqueous or nonaqueous alcohol solvent of up tofour carbon atoms at from about room temperature to the refluxtemperature of the solvent for periods of from one to 48 hours,preferably about 24 hours.

R is hydrogen, lower alkyl, cycloalkyl, aryl, dihalolower alkyl,trihalo-lower alkyl, halo-lower alkyl or adamantyl.

The amidoximes of the formula III are converted to the oxadiazoles ofthe formula IV wherein R is hydrogen by a variety of methods.

a. An amidoxime of the formula III is dissolved in an excess oftri(lower alkyl)orthoformate. preferably triethyl, and heated betweenabout C to about 146C for about 0.5 to about 24 hours. The product ofthe formula IV, either precipitates out, and is separated by filtration,or the excess tri(lower alkyl)orthoformate is removed and the productwashed with an'organic solvent, such as petroleum ether.

b. An amidoxime of the formula III is heated to about 100C with about anequimolar quantity of formic acid for from about one half a minute toten minutes.

c. An amidoxime of the formula III is cyclized by reaction with twomolar equivalents of a complex of dimethylformamide-phosphorusoxychloride in an ether such as tetrahydrofuran, diethyl ether, etc. attemperatures of from about l0 to about room temperature for from oneminute to three hours. After removal of the solvent and washing withwater, the desired compound of formula IV is obtained.

d. An amidoxime of the formula III is dissolved in an inert organicsolvent, preferably an ether, at depressed temperatures (about 1 0C toabout 10C) and reacted with a mixed anhydride of the formula and stirredfor a period of from about five minutes to about three hours.

Oxadiazoles of the formula IV wherein R is lower alkyl, cycloalkyl,adamantyl, halo-lower alkyl, dihalolower alkyl, trihalo-lower alkyl andaryl are prepared by heating a compound of the formula:

with a compound of formula 111,

In many instances the acylating agent may be used in excess thus alsoserving as the solvent medium; however, generally an inert organicsolvent, such as benzene or ether is employed. The temperature rangegenerally employed is either the refluxing temperature of the solvent orabout 100C whichever is the lesser, and the time ranges from about a fewminutes to about eighteen hours. This reaction is preferably conductedin the presence of a catalytic amount of BF -etherate.

Compounds of the type IV are converted to those of the formula V in pooryield, utilizing reducing agents such as PtO /H Na- S O /CH OH, Pd/H N Hand Pd/C.

1 11 w?) N O The compounds of formula [V wherein R is dihalolower alkylor trihalo-lower alkyl when reduced yield the compounds of formula Vwherein R is halo-lower alkyl. In all other cases, the reduction ofcompounds of formula IV yields the corresponding compounds of formula V,i.e. R'-"=R'.

Surprisingly, catalytic reduction using about 5% Pd/C in the presence ofabout 2-5 equivalents of an acid, such hydrochloric acid or sulfuricacid, gives good yields of amino compounds.

The conversion of the amines of formula V into the(isothiocyanophenyl)oxazoles (l) of this invention may be achieved byreacting the amine with:

l CIJCI in a relatively non-polar solvent, such as chloroform, ether,tetrahydrofuran, etc., preferably in the presence of an acid acceptor,such as calcium carbonate, trimethylaminc, etc. at temperatures from 0to 60C. More specific reaction procedures are disclosed in Houben-Weyl,4th Edition, Vol. 9, pages 867 and 88 1955) and the use of acid bindingagents is disclosed in Arch. Pharm. 295, 146-151 (1962).

b. N,N-di(lower alkyl )thiocarbamoyl halide, wherein said halo atom ischlorine or bromine, in an organic solvent, such as benzene, toluene,ethylene dichloride or chlorobenzene at temperatures of from about 40 toabout 200C [J. Org. Chem. 30, 2465 (1965)] c. a bis-thiocarbamoylsulfide of the formula lower alkyl wherein m is one or two and loweralkyl in preferably ethyl in the presence of an hydrogen halide at roomtemperature to the refluxing temperature of the organic solvent used,such as chlorobenzene [Helv. Chim. Acta 49, 1716 (1966)] d.bis-trichloromethyl penta-thiodiperoxycarbomate wherein said amine ispresent in an excess (3:l [(Angew. Chem. 78, 985 (1966)].

e. ammonium rhodanide in the presence of gaseous hydrogen chloride inthe manner shown in British Pat. No. 1,099,768.

f. phosgene and phosphorus pentasulfide in the general manner describedin Houben-Weyl, 4th Edition, Vol. 9, pages 867 and 88 (1955).

g. carbon disulfide in the presence of an inorganic or organic base,such as triethylamine, potassium carbonate, etc. followed by oxidativedehydrosulphurisation with a metal salt (British Pat. No. 793,802) suchas lead, copper, zinc or iron (11]) salts, iodine, alkalimetalhypochlorites or chlorites, preferably the sodium or po tassium salts(French Pat. No. 1,31 1,855), acid halides such as phosgene andphosphorus oxychloride [Chem. Ber. 98, 24252426 1965)], chlorine andammonium sulfide (DAS 1,198,189) or chloramine T (British Pat. No.1,024,913).

h. ammonium rhodanide and benzoyl chloride, followed by thermaldecomposition in a refluxing solvent such as chlorobenzene [Houben-Weyl,4th Edition, 9, 867 and 88 (1955)].

i. carbon disulfide, dicyclohexyl carbodiimide and a tertiary amine suchas pyridine or triethylamine at temperatures of from about 1() to about30C for from about 0.5 to about 24 hours [Chem Ber. 101, 1746 1968)].

The publications cited for the introduction of the isothionato group areincorporated by reference.

Preferred compounds and intermediates prepared by the above proceduresare those wherein R is hydrogen or chlorine; and R is hydrogen,halo-lower alkyl, cycloalkyl, adamantyl, phenyl or substituted phenyl.

The most preferred compounds are those wherein R is hydrogen and R ishydrogen, chloromethy, cyclopropyl, cyclohcxyl, adamantyl, phenyl,3,4,5- trimethoxyphenyl, or p-chlorophenyl; and especially when the5-substituted oxadiazole is located para with respect to theisothiocyanic acid phenyl ester.

The compounds of formula 1 have anthelmintic activity and are useful inthe treatment and/or prevention of helminthiasis, a parasitic diseasewhich causes widespread and often serious infection in domesticatedanimals such as swine, horses, cattle, dogs, cats and sheep. While thecompounds are preferably used in the treatment of hookworm (Ancylostomacanium and Uncinarz'a stenocep/zala) and roundworm (Toxccara Cam's andThrescaris leonl'na), other compounds are also highly useful in treatinginfections caused by haemonchus, ostertagia, trichostrongylus, cooperia,nematodirus, bunostomum, strongylorides, oesophagostomum, trichiuris andmoniezia. In treating domesticated animals, the compounds are givenorally and may be mixed with a nontoxic, edible carrier to form a feedsupplement, or

be administered in unit dosage forms such as powders, capsule, tablet,boluses, drenches, etc.

In general, the compounds of formula 1 exhibit anthelmintic activitywhen administered to animals in a daily dose of about to about 200 mgper kilogram of animal body weight. It is preferred to employ in therange of -100 mg per kilogram of body weight per day. The compounds maybe given in a single dose or divided into a plurality of smaller doses.When the compounds are to be employed primarily as'prophylactic agentsfor the prevention of helminthic' infections, the preferred daily doselevel is, of course, lower than the therapeutic level is, preferably inthe range of about 2-20 mg per kilogram of body weight.

When the compounds of formula I are to be administered in unit dosageform, capsules, boluses or drenches containing the desired amount ofanthelmintic distributed in a pharmaceutically acceptable vehicle areusually employed. These are prepared by intimately and uniformly mixingthe active ingredient with suitable finely divided diluents, suspendingagents, fillers, disintegrating agents and/or binders such as starch,lactose, talc, magnesium stearate, vegetable gums and the like and arecompounded by techniques generally known in the art.

The compounds of formula I may also be administered as a component ofthe feed of the animals or suspended in the drinking water. Thus, novelfeed and feed supplement compositions may be prepared in which thecompounds of this invention are present as an active anthelminticingredient. A typical feed supplement comprises the anthelmintic agent(550 percent, preferably 10-30 percent) intimately dispersed in oradmixed with an inert carrier or diluent, i.e. one that is nonreactivewith respect to the anthelmintic agent and that may be administered withsafety to the animals. The carrier or diluent is preferably one that isor may be an ingredient of an animal ration. This composition may bemixed with the feed to give any useful desired concentration, preferablyabout 0.1-2 percent. Lastly, feeds containing the active ingredient maybe made directly by mixing said active ingredient in a feed which isinert to said anthelmintic compounds so as to give feeds havingconcentrations of anthelmintic agent of from 01-270.

DETAILED DESCRIPTION The following examples are provided forillustrative purposes and may include particular features of theinvention; however, the examples should not be construed as limiting theinvention, many variations of which are possible without departing fromthe spirit or scope thereof. All temperatures are in degrees centigrade.

EXAMPLEI p-Nitrobenzamidoxime A solution of 29.6 g (0.20 mole) ofpnitrobenzonitrile, 13.9 g (0.20 mole) of hydroxylamine, HCL, 13.8 g(0.10 mole) of K2CO in 700 ml of ethanol and 70 ml of H20 is refluxedfor 20 hr, cooled and diluted with 200 ml of H 0. After removal of the'ethanol by distillation in vacuo, the product precipitates out of theaqueous residue. This product is collected by filtration, washed with H0 and dried tov yield 21.6 g (60%).

EXAMPLES 2-9 Substituted-nitrobenzamidoximes According to the proceduresdescribed in example 1, upon substituting in place ofp-nitrobenzonitrile, one of the following:

2-nitro-3-methylbenzonitrile 3-nitro-2-chlorobenzonitrile4-nitro-3-trifluoromethylbenzonitrile 4-nitro-2-ethoxybenzonitrile2-nitro-4-phenylbenzonitri1e 2-nitro-4-phenoxybenzonitrileZ-nitro-4-dimethylaminobenzonitrile and 3-nitro-4-acetamidobenzonitrileone obtains:

2-nitro-3-methylbenzamidoxime, 3-nitro-2-chlorobenzamidoxime,4-nitro-3-trifluoromethylbenzamidoxime, 4-nit1 o-2-ethoxybenzamidoxime,2-nitro-4-phenylbenzamidoxime, 2-nitro-4-phenoxybenzamidoxime2-nitro-4-dimethylaminobenzamidoxime, and3-nitro-4-acetamidobenzamidoxime respectively.

EXAMPLE 10 3-(p-Nitrophenyl 1 ,2,4-oxadiazole A mixture of 2.5 g (1.4 X10 mole) of pnitrobenzamidoxime 0.03 ml of BF Et O and 6.2 g" (4.2 X 10mole) of triethyl orthoformate are heated with stirring until all of theamidoxime has dissolved. Heating is then continued for an additionalminute, at which time the contents of the reaction flask solidifies.This solid is collected, washed with pet. ether and dried to yield 2.2 gof product (82%), mp l6ll64.

EXAMPLE 11 3 ,5-Bis(p-nitrophenyl l ,2,4-oxadiazole A solution of 5.4 g(0.03 mole) of p- EXAMPLE 12 5-(p-Cloropheny1)-3-(p-nitrophenyl)-l,2,4-oxadiazole According to the procedure of example 1 1 and utilizing10.8 g (0.06 mole) of p-nitrobenzamidoxime, 10.6 g (0.06 mole) ofp-chlorobenzoyl chloride and 2 ml of BF -Et O, yielding10.8 g of theproduct.

EXAMPLE 1 3 3-( p-Nitrophenyl )-5 3 ,4,5-trimethoxyphenyl l ,2,4-

oxadiazole According to the procedure of example 1 1 and utilizing 9.0 g(0.05 mole) of p-nitrobenzamidoxime, l 1.5 g

EXAMPLE l4 -Phenyl-3-( p-nitrophenyl l ,2,4-oxadiazole According to theprocedure of example 1 l and utilizing 10.8 g (0.06 mole) ofp-nitrobenzamidoxime, 8.5 g (0.06 mole) of benzoyl chloride and 2 ml ofBE Et O, the above named product is obtained in a yield of 8.1 g (50percent).

EXAMPLES l5-l9 5-( Substituted-phenyl )3-( p-nitrophenyl l ,2,4-oxadiazole According to the procedure described in example 1 1, uponsubstituting in place of the p-nitrobenzoyl chloride, one of thefollowing o-bromobenzoyl chloride p-fluorobenzoyl chloridem-ethylbenzoyl chloride p-trifluoromethylbenzoyl chloride andm-propoxybenzoyl chloride one obtains 5-(o-bromophenyl)-3-(p-nitrophenyl l ,2,4-

oxadiazolc, 5-(p-fluorophenyl)-3-(p-nitrophenyl)-1,2,4-

oxadiazole, 5-( m-ethyl'phenyl )-3-( p-nitrophenyl l ,2,4-oxadiazole,5-( p-trifluoromet'hylphenyl )-3( p-nitrophenyl )-l ,2,4-

oxadiazole, and 5-( m-propoxyphenyl )3-( p-nitrophenyl l ,2,4-

oxadiazole, 40

respectively.

EXAMPLES 20-27 5-Phenyl-3-(substituted-nitrophenyl)- l ,2,4-oxadiazoleAccording to the procedure described in example 1 1, upon substitutingin place of p-nitrobenzamidoxime, the products of examples 29, oneobtains:

5-phenyl-3-(2-nitro-3-methylphenyl) l ,2,4-oxadiazole,5-phenyl'3-(3-nitro-2-chlorophenyl)-1 ,2,4-oxadiazole,5-phenyl-3-(4-nitro-3-trifluoromethylphenyl )-l ,2,4-

oxadiazole, 5-phenyl-3-(4-nitro-2-ethoxyphenyl )-l ,2,4-oxadiazole,5-phenyl-3-( 2-nitro-4-phenylphenyl)- l ,2,4-oxadiazole,5-phenyl-3-(2-nitro-4-phenoxyphenyl)-1,2,4-

oxadiazole, 5-phenyl-3-( 2-nitro-4-dimethylaminophenyl l ,2,4-

oxadiazole, and

5-phenyl-3-( 3-nitro-4-acetamidophenyl l ,2,4-

oxadiazole,

respectively.

Similarly, by employing the substituted-benzoyl chlo- 6 rides taught inexamples 12 to 19 in place of the pnitrobenzoyl chloride other compoundswithin the scope of formula III are prepared.

EXAMPLE 28 lsothiocyanic acid, p-( 1,2,4-oxadiazol-3-yl)phenyl ester Asolution of 4.0 g (0.02 mole) of 3-(p-nitrophenyl)- 1,2,4-oxadiazole(example l0) in 400 ml of ethanol containing 0.04 g of 10% Pd/C ishydrogenated at 50 psi over a period of 1 hr. The catalyst is removed byfiltration followed by removal of the ethanol by distillation in vacuo.The resulting residue is taken up in a mixture of 300 ml of CHCl 100 mlof H 0 containing 3.0 g (0.03 mole) of CaCO This mixture is cooled at 5,followed by the addition of 2.9 g (0.03 mole) of CSCl- After stirringfor 1 hr at this temperature, the mixture is allowed to stir overnightat r.t. The organic layer is then separated, washed with H 0 and driedover CaCl After removing the drying agent, the CHCL; is removed bydistillation in vacuo to yield a solid residue. This residue is washedwith pet. Et O to yield 2.1 g of product 52%), mp 121125.Recrystallization from pet. ether (3060C)-Et2O yields an analyticallypure sample, mp l24l27.

EXAMPLE 29 lsothiocyanic acid, p-( 5-phenyll ,2,4-oxadiazol-3-yl )phenylester A suspension of 5.0 g (0.02 mole) of5-phenyl-3-(pnitrophenyl)-l,2,4-oxadiazole (example 14) in 200 ml ofethanol containing 0.5 g of 5% Pd/C and 3 ml of cone. HCl ishydrogenated at 50 psi over a period of 1 hr. The catalyst is removed byfiltration followed by removal of the ethanol by distillation in vacuo.The resulting residue is taken up in a mixture of 300 ml of CHCl and mlof H 0 containing 2.4 g (0.02 mole) of CaCO This mixture is cooled to 0followed by the addition of 2.5 g (0.02 mole) of CSCl After stirring for15 min at this temperature, the ice bath is removed and the mixture isallowed to stir for an additional 0.5

hr. The reaction mixture is then filtered, and the organic layer isseparated, washed with H 0 and dried over CaCl After removing the dryingagent, the CHCl is removed by distillation in vacuo to yield a solidresidue. This residue is washed with pet. ether (3060C)Et O to yield 3.3g of product (63 percent). Recrystallization from pet. ether (30- 60C)EtO yields an analytically pure sample, mp

EXAMPLE 30 Isothiocyanic acid, p-[ 5-( p-chlorophenyl l,2,4-oxadiazol-3-yl ]-phenyl ester According to the procedure of example29, a suspension of 10.8 g (0.04 mole) of5-(p-chlorophenyl)-3-(pnitrophenyl)-l,2,4-oxadiazole (example 12), L8 gof 5% Pd/C and 5 ml of cone. HCl in 200 ml of EtOH is hydrogenated at 50psi over a period of 1 hr. The resulting amine is reacted with 4.6 g(0.04 mole) of CSCI and 5.0 g (0.05 mole) of Et N in 400 ml of THF and 5yielded 8.2 g (73 percent) of product. Recrystallization from Et Oyields an analytically pure sample, mp

EXAMPLE 31 lsothiocyanic acid, p-[ 3,4,5-trimethoxyphenyl )-1,2,4-oxadiazol-3- yl]phenyl ester According to the procedure of example29, a suspension of 3.6 g (0.01 mole) of 3-(p-nitrophenyl)-5-(3,4,5-trimethoxyphenyl)-l ,2,4-oxadiazole (example 13), 0.4 g of 5% Pd/C and 3ml of cone. HCl in 200 ml of EtOH is hydrogenated at 50 psi over aperiod of 1 hr. The resulting amine is reacted with 1.2 g (0.01 mole) ofCSC1 and 1.3 g (0.01 mole) of Et N in 200 mo of THF and yielded 2.6 g(65%) of product. Recrystallization from Et O yields an analyticallypure sample, mp 160-1 6 1.

EXAMPLE 32 lsothiocyanic acid, p-( 1 ,2,4-oxadiazol-3-yl )phenyl esterAccording to the procedure of example 29, starting with 5.0 g (0.03mole) of 3-(p-nitrophenyl)-l ,2,4- oxadiazole (example 0.5 g of 5% Pd/Cand 6 ml of cone. HCl in 200 ml of 95% EtOH, the reduced material isreacted with 2.5 g (0.02 mole) of CSCI and 2.4 g (0.02 mole) of CaCO in300 ml of CHCl and 100 ml of H 0 to yield 2.7 g of pure product (51percent). Recrystallization from pet. ether (3060C)-Et O yields ananalytically pure sample, mp 128l29.

EXAMPLES 33-40 lsothiocyanic acid,l,2,4-oxadiazol-3-yl)substituted-phenyl esters According to theprocedure of example 29, upon substituting in place of5-phenyl-3-(p-nitrophenyl)- l,2,4-oxadiazole, the products of examples20 to 27, one obtains:

isothiocyanic acid, 2-(5-phenyll ,2,4oxadiazol-3-yl)- 6-methylphenylester,

isothiocyanic acid, 3-(5-phenyl-l,2,4-oxadiazol-3-yl)- 2-chlorophenylester,

isothiocyanic acid, 4-(5-phcnyl-1,2,4-oxadiazol-3-yl)-2-trifluoromethylphenyl ester,

isothiocyanic acid, 4( S-phenyl-l ,2,4-oxadiazol-3-yl 3-ethoxyphenylester,

isothiocyanic acid, 2-(5-phenyl-l,2,4-oxadiazol-3-yl)- 5-(pheny1)phenylester,

isothiocyanic acid, 2-( S-phenyl-l ,2,4-oxadiazol-3-yl 5-(phenoxy)phenylester,

isothiocyanic acid, 2-(5-phenyl-l,2,4-oxadiazol-3-yl)-S-dimethylaminophenyl ester, and

isothiocyanic acid, 3-( S-phenyl-l ,2,4-oxadiazol-3-yl 6-acetamidophenylester, respectively.

EXAMPLE 41 5-Cyclopropyl3(pmitrophenyl l ,2,4-oxadiazole To a solutionof 9.0 g (0.05 mole) of pnitrobenzamidoxime in 500 ml of dioxane thereis added 5.2 g (0.05 mole) of cyclopropanecarboxylic acid chloride andthe mixture is stirred at room temperature for 5 minutes, followed byaddition of 2 ml of BF Et O. The mixture is refluxed for 18 hours,cooled, and H 0 is added. The resulting precipitate is filtered off,dried, and crystallized from Et- O to yield 7.3 g of product (63%) mpl54l56.

EXAMPLE 42 5-Cyclohexyl-3-(p-nitrophenyl l ,2,4-oxadiazole Following theprocedure of example 41 and using 9.0 g (0.05 mole) ofp-nitrobenzamidoxime, 7.3 g (0.05 mole) of cyclohexylcarboxylic acidchloride, and 2 ml of BF -,Et O yield 8.1 g (60 percent) of product,crystallized from Et O, mp 1 14] 16.

EXAMPLE 43 5-( l-Adamantyl )-3-(p-nitrophenyl )-l ,2,4-oxadiazoleFollowing the procedure of example 41, 9.0 g (0.05 mole) ofp-nitrobenzamidoxime, 10.0 g (0.05 mole) of l-Adamantanecarboxylic acidchloride, and 2 ml of BF Et O yield 6.4 g (40 percent) crystallized fromEt O, mp 202204.

EXAMPLES 44-5 1 5-( Alkyl or cycloalkyl )-3-( p-nitrophenyl)- 1,2,4-oxadiazole According to the procedure of example 41, uponsubstituting in place of cyclopropanecarboxylic acid chloride, one ofthe following:

cyclobutylcarboxylic acid chloride, cyclopentylcarboxylic acid chloride,acetyl chloride,

propionyl chloride,

butyryl chloride,

i-butyryl chloride,

valeric chloride, and

i-valeric chloride one obtains:

5-cyclobutyl- 3-(p-nitrophenyl l ,2,4-oxadiazole 5-cyclopentyl-3-(p-nitrophenyl )-l ,2,4-oxadiazole5-methyl-3-(p-nitrophenyl)-1,2,4-oxadiazole 5-ethyl-3-( p-nitrophenyl)-l ,2,4-oxadiazole 5-propyl-3-(p-nitrophenyl)-1,2,4-oxadiazole5-isopropyl-3-(p-nitrophenyl l ,2,4-oxadiazole 5-butyl-3-(p-nitrophenyl)-1 ,2,4-oxadiazole and 5-isobutyl-3-( p-nitrophenyl )-1 ,2,4-oxadiazolerespectively.

EXAMPLE 52 lsothiocyanic acid, p-( 5-cyclopropyl-l ,2,4-oxadiazol-3-yl)-phenyl ester A mixture of 2.3 g (0.01 mole) of 5-cyclopropyl-3-(p-nitrophenyl)-1,2,4-oxadiazole, 0.25 g of 5% Pd/C, 5 ml of 10% HCl,and 195 ml of absolute ethanol is hydrogenated on the Parr hydrogenatorat 50 psi until the theoretical amount of hydrogen is absorbed. Themixture is filtered and the solvent is removed in vacuo. The residue istaken up in 60 ml H 0 and ml glyme and neutralized with saturated NaHCOThen there is added 1.0 g (0.01 mole) of CaCO and then 0.8 ml ofthiophosgene at 0C and the mixture is stirred for 1.5 hour. The solventis removed in vacuo at room temperature. The residue is dried andcrystallized from Et O to yield 1.3 g (54 percent) of product, mp 82-84.

EXAMPLE 53 lsothiocyanic acid, p-( -cyclohexyll ,2,4-oxadiazol-3-yl)-phenyl ester Following the procedure of example 52, 2.73 g (0.01 mole)of 5-cyclohexyl-3-(p-nitrophenyl )-l ,2,4- oxadiazole, 0.3 g (5%) Pd/C,5 ml of HCl, 1.0 g CaCO and 0.8 ml thiosphosgene gives a solid residuewhich is chromatographed on Alumina Act IV. Elution with PE (3060C)yields 1.4 g (50 percent) of product, cyrstallized from PE, mp 5557.

EXAMPLE 54 lsothiocyanic acid, p-[ 5( l-adamantyl )-l,2,4-oxadiazol-3-yl ]-phenyl ester Following the procedure of example52, 3.2 g (0.01 mole) of 5-( l-adamantyl)-3-(p-nitrophenyl)-l,2,4-oxadiazole, 0.3 g of 5% Pd/C, 5 m1 of 10% HCl, 1.0 g of CaCO and 0.8 mlthiophosgene yields 1.3 g (38 percent) of the product, crystallized fromPE 306()C), mp l40-143.

EXAMPLES 55-62 lsothiocyanic acid, p-[5-(alkyl or cycloalkyl l,2,4-oxadiazol-3-yl ]phenyl ester According to the procedure of example52, upon substituting in place of the5-cyclopropyl-3-(pnitrophenyl)-l,2,4-oxadiazole, the products ofexamples 44-51, one obtains:

p-(S-propyl-1,2,4-oxadiazol-3- isothiocyanic acid,p-(S-butyl-l,2,4-oxadiazol-3-yl)- 2 phenyl ester, and isothiocyanicacid,

yl)phenyl ester p-( 5-isobutyl- 1 ,2,4-oxadiazol-3- and diluted withwater. The resulting precipitate is collected and washed with ether toyield 1 l .2 g of product.

EXAMPLES 64-67 3-(p-Nitrophenyl )-5-Haloalkyl-l ,2,4oxadiazole Accordingto the procedure of example 63 upon substituting for trichloroacetylchloride one of the followtribromoacetyl chloride 2,2-dibromopropionylchloride 3,3,3-trichlorobutyryl chloride 4,4,4-trichlorovaleryl chlorideone obtains 3-(p-nitrophenyl)-5-tribromomethyl-1,2,4-oxadiazole,

3-( p-nitrophenyl )-5-( 2,2-dibromoethyl l ,2,4-

oxadiazole,

3-( p-nitrophenyl )-5-( 3,3,3-trichloropropyl )-l ,2,4-

oxadiazole,

3-(p-nitrophenyl)-5-(4,4,4-trichlorobutyl)-1,2,4-

oxadiazole and respectively.

Similarly by employing the substitutednitrobenzamidoximes of examples 2to 9 for the pnitrobenzamidoxime in examples 63-67, other compoundswithin the scope of formula lll are prepared.

EXAMPLE 68 lsothiocyanic acid, p- 5-( chloromethyl )-l,2,4-oxadiazol-3-yl -pheny] ester A suspension of 6.2 g (0.02 mole) of3-(pnitrophenyl )-5-trichloromethyl-l ,2,4-oxadiaz0le from example 63,0.6 g of 5% Pd/C, and 2 ml of concentrated HCl in 200 ml of ethanol ishydrogenated at 50 psi over a period of two hours. The resulting amine,3- (p-aminophenyl )-5-chloromethyl-l ,2,4-oxadiazole, is reacted with2.5 g (0.02 mole) of CSCl and 2.5 g (0.03 mole) of CaCO in a mixture ofml of CHCl and 30 ml of water. The solvent is removed to yield 2.6 g (52percent) of product. Recrystallization from pet. ether yields ananalytical sample; mp lO8l 10.

EXAMPLES 6972 lsothiocyanic acid,

p-[ 5-( haloalkyl l ,2,4-oxadiazol-3-yl ]-phenyl ester According to theprocedure described in example 68, upon substituting in place of3-(p-nitrophenyl)-5-trichloromethyl-1,2,4-oxadiazole the product ofexamples 64-67 one obtains:

isothiocyanic acid, p- 5-( bromomethyl l ,2,4-

oxadiazol-3-yl]phenyl ester,

oxadiazol-3-yl1phenyl ester, and isothiocyanic acid, p-[5-(4-chlorobutyl l ,2,4-

oxadiazol-3-yl]phenyl ester.

What is claimed is: l. A compound of the formula SCN I and R is selectedfrom the group consisting of hydrogen, lower alkyl, cycloalkyl of 3 to 6carbons, adamantyl, halo-lower alkyl, phenyl and substituted phenylwherein said substituent is chloro, bromo, fluoro, lower alkyl, loweralkoxy, 3,4,5-trimethoxy, or trifiuoromethyl.

2. The compound of claim 1 wherein R is selected from the groupconsisting of hydrogen and chlorine; and R is selected from the groupconsisting of hydrogen, halo-lower alkyl, cycloalkyl of 3 to 6 carbons,adamantyl, phenyl and substituted phenyl wherein said substituent ischloro, bromo, fluoro, lower alkyl, lower alkoxy, 3,4,5-trimethoxy, ortrifluoromethyl.

3. The compound of claim 1 having the name isothiocyanic acid,p-(S-ethyl-l ,2,4-oxadiazol-3-yl)phenyl ester.

4. The compound of claim 2 wherein R is chloro and R is phenyl.

5. A compound of the formula SCN wherein R is selected from the groupconsisting of hydrogen, chloromethyl, phenyl, 3,4,5-trimethoxyphenyl,p-chlorophenyl, cyclopropyl, cyclohexyl and adamantyl.

6. The compound of claim 5 having the name isothiocyanic acid,p-(l,2,4-oxadiazol-3-yl)phenyl ester.

7. The compound of claim 5 having the name isothiocyanic acid,p-(S-phenyl-l,2,4-oxadiazol-3-yl)phenyl ester.

8. The compound of claim 5 having the name isothiocyanic acid,p-[5-(p-chlorophenyl)-1,2,4-oxadiazol-3- yl]phenyl ester.

9. The compound of claim 5 having the name isothiocyanic acid,p-[5-(3,4,5-trimethoxyphenyl l ,2,4- oxadiazol-3-yl]phenyl ester.

10. The compound of claim 5 having the name isothiocyanic acid,p-(S-cyclopropyll ,2,4-oxadiazol-3- yl)phenyl ester.

1 1. The compound of claim 5 having the name isothiocyanic acid,p-(5-cyclohexyl-1,2,4-oxadiazol-3- yl)phenyl ester.

12. The compound of claim 5 having the name isothiocyanic acid, p-[5-(1-adamantyl)-1 ,2,4-oxadiazol-3- yl]phenyl ester.

13. The compound of claim 5 having the name isothiocyanic acid, p-[5-(chloromethyl l ,2,4-oxadiazol-3- yl]phenyl ester.

UNITE?) FATE??? AND TRiLl-EMARK OFFICE TER'HFlCATE 9F CQRRECTIQN PAz'FN'i NO. 3,910,942

:M ENEORG) 1 Narayanan, v k h L. et 81 :a tified error appears in theabove-identified patent and that said Letters Patent aw hereby correctedas shown beiow:

Col. 1, line 31, "isothlocyanophenyl" should read isothiocyanophenyl.

Col. 3 line 45, "chloromethy" should read chloromethyl--.

Col. 8, line 7, "0.04" should read -O.4-.

Col. 11, line 7, "thiosphosgene" should read thiophosgene-.

Col. 11, line 35, "ethyl" should read --methyl.

Col. ll, line 37, "propyl" should read ethyl.

Col. 12, line 12, "oxadiazole," should read oxadiazole, and.

Col. 12, line 14, "oxadiazole and" should read oXadiazole-.

Signed and Sealed thisthirtieth D a); of March 1 976 [SEAL] Arrest:

RUTH c. MASON c. MARSHALL DANN Arresting Officer (mnmissiuner oj'laremsand Trademarks PATENT NO. 3 910 942 9A: r-qo 10/7/75 rrwmromsr Naray nVenkatachala L. et 31 5r 5; certified *2? error appears in theabove-identified patent and that saidLetters Patent are hereby correctedas ShOWI'I below:

Col. 1, line 31, "isothlocyanophenyl" should read -isothiocyanophenyl.

Col. 3, line 45, "chloromethy" should read -chloromethyl-.

Col. 8, line 7, "0.04" should read --O.4--.

Col. 11, line 7, "thiosphosgene" should read -thiophosgene.

Col. 11, line 35, "ethyl" should read methyl-.

Col. 11, line 37, "propyl" should read ethyl-.

Col. 12, line 12, "oxadiazole," should read -oxadiazole, and.

Col. 12, line 14, "'oxadiazole and" should read -oxadiazole-.

Signed and Sealed thisthirtieth D f March 1976 [SEAL] A ttes t:

RUTH C. MASON C. MARSHALL DANN Arresting Officer (ummr'ssinneroj'Patents and Trademarks

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 wherein R isselected from the group consisting of hydrogen and chlorine; and R1 isselected from the group consisting of hydrogen, halo-lower alkyl,cycloalkyl of 3 to 6 carbons, adamantyl, phenyl and substituted phenylwherein said substituent is chloro, bromo, fluoro, lower alkyl, loweralkoxy, 3,4,5-trimethoxy, or trifluoromethyl.
 3. The compound of claim 1having the name isothiocyanic acid,p-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl ester.
 4. The compound of claim 2wherein R is chloro and R1 is phenyl.
 5. A compound of the formula 6.The compound of claim 5 having the name isothiocyanic acid,p-(1,2,4-oxadiazol-3-yl)phenyl ester.
 7. The compound of claim 5 havingthe name isothiocyanic acid, p-(5-phenyl-1,2,4-oxadiazol-3-yl)phenylester.
 8. The compound of claim 5 having the name isothiocyanic acid,p-(5-(p-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenyl ester.
 9. The compoundof claim 5 having the name isothiocyanic acid,p-(5-(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazol-3-yl)phenyl ester.
 10. Thecompound of claim 5 having the name isothiocyanic acid,p-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)phenyl ester.
 11. The compound ofclaim 5 having the name isothiocyanic acid,p-(5-cyclohexyl-1,2,4-oxadiazol-3-yl)phenyl ester.
 12. The compound ofclaim 5 having the name isothiocyanic acid,p-(5-(1-adamantyl)-1,2,4-oxadiazol-3-yl)phenyl ester.
 13. The compoundof claim 5 having the name isothiocyanic acid,p-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)phenyl ester.